STUDY QUESTION Does adjuvant growth hormone (GH) therapy in GnRH antagonist cycles improve reproductive outcomes in the general IVF population? SUMMARY ANSWER Empiric adjuvant GH therapy in GnRH antagonist cycles does not improve IVF stimulation results or reproductive outcomes, including implantation, miscarriage, and clinical pregnancy rates. WHAT IS KNOWN ALREADY Previous evidence regarding the benefits of GH therapy in IVF cycles has been inconclusive due to the lack of well-designed, large-scale randomized controlled trials (RCTs) in the general IVF population. STUDY DESIGN, SIZE, DURATION This is a phase III open-label RCT involving 288 patients undergoing antagonist IVF cycles at the Ovo clinic in Montreal, Canada, between June 2014 and January 2020. Patients were randomly assigned at a 1:1 ratio to either the GH or control group. The intervention group received daily 2.5 mg subcutaneous injections of GH from Day 1 of ovarian stimulation until the day of oocyte retrieval, while the control group received standard ovarian stimulation without any adjuvant therapy. PARTICIPANTS/MATERIALS, SETTING, METHODS Patients were expected normal responders. All embryo transfers, both fresh and frozen, resulting from the studied IVF cycle were included in an intention-to-treat and per-protocol analyses. The primary outcome was the clinical pregnancy rate, while secondary outcomes included the number of retrieved oocytes, good-quality embryos, maturation, fertilization, implantation, and miscarriage rates. MAIN RESULTS AND THE ROLE OF CHANCE A total of 288 patients were recruited and randomly assigned at a 1:1 ratio to either the GH or the control group. After excluding cycle cancellations and patients who did not undergo transfer, 105 patients remained in each group. The overall mean age was 38.0 years, the mean BMI was 25.11 kg/m2 and the mean anti-Müllerian hormone was 2.51 ng/ml. The cycle characteristics were similar between both groups. No differences were observed regarding the total dose of gonadotropins (4600 versus 4660 IU for the GH and control groups, respectively, P = 0.752), days of stimulation (11.4 versus 11.7 days, P = 0.118), and endometrial thickness (10.63 versus 10.94 mm, P = 0.372). Both the intention to treat (ITT) and per protocol analyses yielded similar results for stimulation outcomes. In the ITT analysis, no differences were found in the number of follicles ≥15 mm (7.8 versus 7.1, P = 0.212), retrieved oocytes (11.7 versus 11.2, P = 0.613), mature oocytes (8.5 versus 8.6, P = 0.851), maturation rate (73.8 versus 78.4%, P = 0.060), fertilization rate (64.3 versus 67.2%, P = 0.388), and good quality embryos (2.5 versus 2.6, P = 0.767). Reproductive outcomes in fresh embryo transfer showed no difference for implantation rate (38.2 versus 39.5%, P = 0.829), miscarriage rate (26.5 versus 31.1%, P = 0.653), clinical pregnancy rate (43.6 versus 50.0%, P = 0.406, rate difference, 95% CI: −0.06 [−0.22, 0.09]), and live birth rate (32.1 versus 33.3%, P = 0.860). The number of embryos needed to achieve a clinical pregnancy was 3.0 versus 2.5 in the GH and control groups, respectively. Similarly, reproductive outcomes in first frozen embryo transfer showed no difference for implantation rate (31.6 versus 45.3%, P = 0.178), miscarriage rate (28.6 versus 26.3%, P = 0.873), clinical pregnancy rate (35.1 versus 44.2%, P = 0.406, P = 0.356, rate difference, 95% CI: −0.09 [−0.28, 0.10]), and live birth rate (22.8 versus 32.6%, P = 0.277). The number of embryos needed to achieve a clinical pregnancy was 3.1 versus 2.4 in the GH and control groups, respectively. LIMITATIONS, REASONS FOR CAUTION The study focused on expected normal responders, limiting its applicability to other patient populations such as poor responders. WIDER IMPLICATIONS OF THE FINDINGS These findings suggest that adding GH therapy to ovarian stimulation in GnRH antagonist cycles may not benefit the general IVF population. Additional high-quality RCTs are warranted to identify subgroups of patients who might benefit from this treatment. STUDY FUNDING/COMPETING INTEREST(S) EMD Serono Inc., Mississauga, Canada, supplied Saizen® for the study, free of charge. In addition, they provided funding for the statistical analysis. I-J.K. declares grants or contracts from Ferring Pharmaceuticals, consulting fees from Ferring Pharmaceuticals, honoraria from Ferring Pharmaceuticals and EMD Serono, support for attending meetings or travel from Ferring Pharmaceuticals and EMD Serono, participation on a Data Safety Monitoring Board or Advisory Board for Ferring Pharmaceuticals, and stock or stock options from The Fertility Partners; W.J. declares support for attending meetings or travel from EMD Serono; and S.P. declares stock or stock options from The Fertility Partners. All other authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER NCT01715324. TRIAL REGISTRATION DATE 25 October 2012. DATE OF FIRST PATIENT’S ENROLMENT 25 June 2014.

中文翻译：

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在 IVF 中经验性使用生长激素是没有用的：最大的随机对照试验


研究问题 GnRH 拮抗剂周期中的辅助生长激素 （GH） 治疗是否能改善一般 IVF 人群的生育结局？摘要答案 GnRH 拮抗剂周期的经验性辅助 GH 治疗不会改善 IVF 刺激结果或生殖结局，包括植入、流产和临床妊娠率。已经知道的 由于在一般 IVF 人群中缺乏精心设计的大规模随机对照试验 （RCT），因此先前关于 GH 疗法在 IVF 周期中益处的证据尚无定论。研究设计、规模、持续时间 这是一项 III 期开放标签随机对照试验，涉及 2014 年 6 月至 2020 年 1 月期间在加拿大蒙特利尔 Ovo 诊所接受拮抗剂 IVF 周期的 288 名患者。患者以 1：1 的比例随机分配到 GH 组或对照组。干预组从卵巢刺激第 1 天到取卵当天每天皮下注射 2.5 mg GH，而对照组接受标准卵巢刺激，没有任何辅助治疗。参与者/材料、设置、方法 患者是预期的正常反应者。由所研究的 IVF 周期产生的所有胚胎移植，包括新鲜和冷冻胚胎，均被纳入意向治疗和按方案分析。主要结局是临床妊娠率，而次要结局包括取回的卵母细胞数量、优质胚胎、成熟、受精、着床和流产率。主要结果和机会的作用 共招募了 288 名患者，并以 1：1 的比例随机分配到 GH 组或对照组。在排除周期取消和未接受转移的患者后，每组仍有 105 名患者。 总平均年龄为 38.0 岁，平均 BMI 为 25.11 kg/m2，平均抗苗勒管激素为 2.51 ng/ml。两组之间的周期特征相似。在促性腺激素的总剂量 （GH 组和对照组分别为 4600 和 4660 IU，P = 0.752）、刺激天数 （11.4 天 vs 11.7 天，P = 0.118） 和子宫内膜厚度 （10.63 vs 10.94 mm，P = 0.372） 方面未观察到差异。意向治疗 （ITT） 和根据方案分析对刺激结局产生了相似的结果。在 ITT 分析中，卵泡数量 ≥15 毫米（7.8 对 7.1，P = 0.212）、取回的卵母细胞（11.7 对 11.2，P = 0.613）、成熟卵母细胞（8.5 对 8.6，P = 0.851）、成熟率（73.8 对 78.4%，P = 0.060）、受精率（64.3 对 67.2%，P = 0.388）和优质胚胎（2.5 对 2.6，P = 0.767）。新鲜胚胎移植的生殖结局显示，植入率 （38.2 vs 39.5%，P = 0.829） 、流产率 （26.5 vs 31.1%，P = 0.653）、临床妊娠率 （43.6 vs 50.0%，P = 0.406，率差异，95% CI： -0.06 [-0.22， 0.09]）和活产率 （32.1 vs 33.3%，P = 0.860） 没有差异。GH 组和对照组实现临床妊娠所需的胚胎数量分别为 3.0 和 2.5。同样，第一次冷冻胚胎移植的生殖结果显示植入率 （31.6 对 45.3%，P = 0.178）、流产率 （28.6 对 26.3%，P = 0.873）、临床妊娠率 （35.1 对 44.2%，P = 0.406，P = 0.356，率差，95% CI： -0.09 [-0.28， 0.10]）和活产率 （22.8 对 32.6%，P = 0.277）。实现临床妊娠所需的胚胎数量为 3.1 比 2。GH 组和对照组分别为 4。局限性，谨慎的原因 该研究侧重于预期的正常反应者，限制了其对其他患者群体的适用性，例如反应不佳的人。研究结果的更广泛意义这些发现表明，在 GnRH 拮抗剂周期中将 GH 疗法添加到卵巢刺激中可能对一般 IVF 人群没有好处。需要额外的高质量 RCT 来确定可能从这种治疗中受益的患者亚组。研究资金/利益争夺 加拿大密西沙加的 EMD Serono Inc. 为这项研究免费提供了 Saizen®。此外，他们还为统计分析提供了资金。I-J.K. 宣布辉凌制药的赠款或合同、辉凌制药的咨询费、辉凌制药和 EMD 雪兰诺的酬金、辉凌制药和 EMD 雪兰诺对参加会议或差旅的支持、参与辉凌制药的数据安全监测委员会或咨询委员会，以及 The Fertility Partners 的股票或股票期权;W.J. 宣布支持 EMD 雪兰诺参加会议或旅行;和 S.P. 宣布 The Fertility Partners 的股票或股票期权。所有其他作者没有需要披露的利益冲突。试验注册号 NCT01715324。试验注册日期 2012 年 10 月 25 日。首位患者入组日期 2014 年 6 月 25 日。